My name is Emily Messner, and I am a senior graduating from Drexel University with a degree in chemistry. I started working on the CombiUgi project in Dr. Bradley’s laboratory in September 2007. My experience here has reinforced the principles I learned during my co-ops. Organization and understanding the effectiveness of methods are the keys to running effective experiments. I have completed eighteen experiments in the UsefulChem wiki, and I feel as though I have learned a great deal as a part of this research group.
Everything is available as an Opensource approach to chemistry in a wiki format, so editing can be done as experiments progress. Also, when dealing with so many different combinations of starting materials to generate Ugi products, it is much easier to file everything appropriately into Google documents. I have used various database programs during my work experience, but this was my first time adding the details of my experiments into a wiki. The result is a very interesting “laboratory notebook” in which you can keep track of everything in a neat manner, generally avoiding the messy format of a paper notebook.
The Ugi reaction was also a new experience for me. It is a relatively simple procedure to perform, but there are many unknown aspects which we have been able to further investigate. The multi-component reaction involves the addition of an amine, an aldehyde, an acid and an isocyanide to a solvent (usually methanol). If a clear solution can be obtained using a specific set of starting materials, there is a chance that a solid Ugi product will form.
Experimental
Investigation of Data Trends
There were many interesting trends in the data that has been collected. Although the Ugi reaction is not difficult to perform, there are still many aspects which we have been able to further investigate. Some of these aspects include the concentration of the starting materials in the solvent, which solvents can be used, and the kinetics of the reaction. When I started my experiments, there was an issue with the phenanthrene-9-carboxaldehyde. After taking an HNMR, Khalid helped us determine that the aldehyde we thought we were using was not what was actually in the container. Once a new container was ordered from Sigma-Aldrich, an HNMR of the new aldehyde was obtained, and it was determined that this was a pure compound.
There are a few solid products which were formed using phenanthrene-9-carboxaldehyde:
This shows that phenanthrene-9-carboxaldehyde is soluble in methanol and furfurylamine with various different acids and two different isocyanides.
There are also some notable trends for the experiments in which the starting materials were insoluble and included phenanthrene-9-carboxaldehyde. Here are the completed experiments where this was the case:
In each experiment where phenanthrene-9-carboxaldehyde was used with furfurylamine and without phenylacetic acid, a product was never formed. It is also important to note that in each experiment where phenanthrene-9-carboxaldehyde was added to methanol and furfurylamine, the final solution was clear, and Exp178 resulted in a solid product. There must be high solubility between the five membered, oxygen containing ring of furfurylamine and the three bulky aromatic rings of the phenanthrene-9-carboxaldehyde. The location of the nitrogen in the amines seems to determine whether or not phenanthrene-9-carboxaldehyde will dissolve in it. According to the mechanism proposed by Keating and Armstrong, phenanthrene-9-carboxaldehyde might be more soluble when the nitrogen in the amine is not part of a ring structure. When aniline is used, the electron donating nitrogen atom is part of the ring. However, for methylamine and heptylamine, it seems to depend upon the acid which was added after the aldehyde. When furoic acid was used with heptylamine and phenanthrene-9-carboxaldehyde, the reagents were insoluble. When it was used with acetic acid and crotonic acid, clear solutions were obtained. This is perhaps due to the structures of the acids: furoic acid is the only one that contains a ring, and there is also an oxygen atom on the ring.
Experiment 148
I performed Exp148 with Khalid during my first term working on this project. The starting materials in this experiment were phenanthrene-9-carboxaldehyde, heptylamine, tert-butylisocyanide and crotonic acid. A solid ugi product was formed and isolated. This experiment was actually a repeat of Exp143a because of the impure aldehyde. The HNMR of the compound was found to match what was expected. Here is an image where each hydrogen is visible, and I will try to decipher the pattern of the NMR as it was taken in CDCl3 (with help from Khalid):
I believe that the peaks in the aromatic region from 7.96 to 9.58 are representative of the hydrogens on the phenanthrene-9-carboxadehyde. The hydrogens that are part of the chain of the heptylamine are indicated by the peaks from 0.58 to 0.89. The doublet peaks at 1.89 are from the CH3 from the crotonic acid. The peak at 1.39 corresponds to the hydrogens from the tert-butyl isocyanide. I had a more difficult time associating the colored hydrogens from the figure above with the appropriate peaks. I believe that the hydrogen which has been colored blue relates to the sextet at 7.60. The pink colored hydrogen should be the sextet at 7.07. The green colored hydrogen should relate to the peak at 6.88. The red colored hydrogen should relate to the peak at 5.79.
Experiment 150
I also performed Exp150 with help from Khalid, and it yielded a solid Ugi product. It is similar to experiment 148 which also produced a solid Ugi product. The starting materials in this experiment were phenanthrene-9-carboxaldehyde, benzylamine, tert-butylisocyanide and crotonic acid. This was a repeat of Exp143c which made use of the impure aldehyde. Here is an image where each hydrogen is visible in the NMR as it was taken in CDCl3 (with help from Khalid):
The only difference between this structure and that of experiment 148 is the benzylamine. It is interesting that the starting materials for each of these experiments went into solution and formed solid products. The phenanthrene-9-carboxaldehyde is frequently difficult to get into solution following some of the amines.
Solubility
By making use of the Ugi Workflows table, you can see solubility trends beyond the ones I have noted previously. Some intriguing ones deal with phenanthrene-9-carboxaldehyde, which has been in integral part of many of the Ugi products that were made. More products have been formed using phenanthrene-9-carboxaldehyde than any other single aldehyde.
I planned experiments 184 and 186 to see the solubility properties of previous experiments in three solvents other than methanol. In experiment 184, I repeated the starting materials from experiment 183, which did not go into solution in methanol.
I was curious to see which starting materials if any would form a clear solution in ethanol, acetonitrile, and dichloromethane. In experiment 184, phenanthrene-9-carboxaldehyde, cyclohexylamine, mandelic acid (2-hydroxy-2-phenylacetic acid) and t-butyl isocyanide were added to each of those three solvents. In Exp183, the cyclohexylamine went into solution in the methanol, but the addition of phenanthrene-9-carboxaldehyde made a cloudy solution which did not clear up with the addition or the acid and isocyanide or with vortexing. In Exp184, the vials containing ethanol and acetonitrile followed the same pattern; the addition of phenanthrene-9-carboxaldehyde made a cloudy solution. However, in the vial containing dichloromethane, a clear solution was obtained following the addition of phenanthrene-9-carboxaldehyde and vortexing for three minutes. As a result, the reagents were still insoluble in each of the three alternative solvents. This acid may not have been the best choice, because it is bulky and has eight carbon atoms. Although it is soluble in water and most organic solvents, it is insoluble in a clear mixture of methanol and cyclohexylamine.
In Exp186, I wanted to see if 1-pyrenebutyric acid would go into solution in a different solvent. I repeated the starting materials from Exp181-83, using benzaldehyde, aniline, 1-pyrenebutyric acid and n-butylisocyanide in ethanol, acetonitrile and dichloromethane. After the aniline and benzaldehyde were each added to the three solvents, clear solutions were obtained. However, once the 1-pyrenebutyric acid was added to each solution, no clear solution could be obtained after vortexing. Even with the addition of n-butylisocyanide, the three vials remained unclear.
I plan on performing a few more experiments that have been performed previously in methanol in ethanol, acetonitrile and dichloromethane. It would be interesting to repeat an experiment that produced a Ugi product in methanol.
Organization
Another important aspect of research was maintaining the organization of each aspect of all the experiments. The UgiWorkflows Google Doc needed to be updated with scripts pages for some of the previously added experiments. This is a very time consuming process, but it needs to be done. The scripts pages will hopefully be used in the future as a part of an automated process in which a robot can add pre-made solutions of each compound into vials. For each picture that is added into the UgiWorkflows table, there is also a corresponding script page which contains the amount of each compound added and the InChiKey for each one. If the Google Docs are not properly organized and formatted, they can't be optimally used, because the sorting options will not take into account any errors that were made during input. The CombiUgiResults document is also important, because it is a great way to compare the concentrations of experiments that formed a Ugi product to experiments that did not. A whole series of exploratory experiments could be built around determining the optimum concentrations to use for all of the starting materials in the table.
Conclusion
Concerning, the CombiUgi project, I have found that it is more difficult to keep up with each aspect of the experiments unless they are taken care of right away. The really convenient part about using Google documents to track each experiment is the ease of adding new columns of information. It is also a helpful way to share your experiments with other researchers and in turn use data that has been beneficial in other experiments. Because the documents can be exported from Google to a Microsoft Excel spreadsheet, it is possible to sort the data by column and find various trends. Some important trends have concerned the solubility of starting materials and the formation of solid products, and there is an opportunity for many different experiments to be performed regarding solubility and concentrations.
This research project was also a great way to learn about ChemSpider and apply it to my experiments. After becoming a member of ChemSpider, I was able to upload Ugi products onto their server. Then, all of the data for that product can be found in one place. Also, once a molecule has been saved in Chemspider, the InChi and SMILES notations can be exported into ChemSketch to make up a scheme for the reaction. It was great to learn the ways that you can tie everything together and apply various organizational techniques to your data once you've completed an experiment. The CombiUgi project has been an interesting experience where I've learned all about using a wiki, the Ugi reaction, and the useful organization of Google Docs.
My name is Emily Messner, and I am a senior graduating from Drexel University with a degree in chemistry. I started working on the CombiUgi project in Dr. Bradley’s laboratory in September 2007. My experience here has reinforced the principles I learned during my co-ops. Organization and understanding the effectiveness of methods are the keys to running effective experiments. I have completed eighteen experiments in the UsefulChem wiki, and I feel as though I have learned a great deal as a part of this research group.
Everything is available as an Opensource approach to chemistry in a wiki format, so editing can be done as experiments progress. Also, when dealing with so many different combinations of starting materials to generate Ugi products, it is much easier to file everything appropriately into Google documents. I have used various database programs during my work experience, but this was my first time adding the details of my experiments into a wiki. The result is a very interesting “laboratory notebook” in which you can keep track of everything in a neat manner, generally avoiding the messy format of a paper notebook.
The Ugi reaction was also a new experience for me. It is a relatively simple procedure to perform, but there are many unknown aspects which we have been able to further investigate. The multi-component reaction involves the addition of an amine, an aldehyde, an acid and an isocyanide to a solvent (usually methanol). If a clear solution can be obtained using a specific set of starting materials, there is a chance that a solid Ugi product will form.
Experimental
Investigation of Data Trends
There were many interesting trends in the data that has been collected. Although the Ugi reaction is not difficult to perform, there are still many aspects which we have been able to further investigate. Some of these aspects include the concentration of the starting materials in the solvent, which solvents can be used, and the kinetics of the reaction. When I started my experiments, there was an issue with the phenanthrene-9-carboxaldehyde. After taking an HNMR, Khalid helped us determine that the aldehyde we thought we were using was not what was actually in the container. Once a new container was ordered from Sigma-Aldrich, an HNMR of the new aldehyde was obtained, and it was determined that this was a pure compound.
There are a few solid products which were formed using phenanthrene-9-carboxaldehyde:
Here are the completed experiments where all of the reagents went completely into solution but did not produce a Ugi product:
There are also some notable trends for the experiments in which the starting materials were insoluble and included phenanthrene-9-carboxaldehyde. Here are the completed experiments where this was the case:
Experiment 148
I performed Exp148 with Khalid during my first term working on this project. The starting materials in this experiment were phenanthrene-9-carboxaldehyde, heptylamine, tert-butylisocyanide and crotonic acid. A solid ugi product was formed and isolated. This experiment was actually a repeat of Exp143a because of the impure aldehyde. The HNMR of the compound was found to match what was expected. Here is an image where each hydrogen is visible, and I will try to decipher the pattern of the NMR as it was taken in CDCl3 (with help from Khalid):
I believe that the peaks in the aromatic region from 7.96 to 9.58 are representative of the hydrogens on the phenanthrene-9-carboxadehyde. The hydrogens that are part of the chain of the heptylamine are indicated by the peaks from 0.58 to 0.89. The doublet peaks at 1.89 are from the CH3 from the crotonic acid. The peak at 1.39 corresponds to the hydrogens from the tert-butyl isocyanide. I had a more difficult time associating the colored hydrogens from the figure above with the appropriate peaks. I believe that the hydrogen which has been colored blue relates to the sextet at 7.60. The pink colored hydrogen should be the sextet at 7.07. The green colored hydrogen should relate to the peak at 6.88. The red colored hydrogen should relate to the peak at 5.79.
Experiment 150
I also performed Exp150 with help from Khalid, and it yielded a solid Ugi product. It is similar to experiment 148 which also produced a solid Ugi product. The starting materials in this experiment were phenanthrene-9-carboxaldehyde, benzylamine, tert-butylisocyanide and crotonic acid. This was a repeat of Exp143c which made use of the impure aldehyde. Here is an image where each hydrogen is visible in the NMR as it was taken in CDCl3 (with help from Khalid):
The only difference between this structure and that of experiment 148 is the benzylamine. It is interesting that the starting materials for each of these experiments went into solution and formed solid products. The phenanthrene-9-carboxaldehyde is frequently difficult to get into solution following some of the amines.
Solubility
By making use of the Ugi Workflows table, you can see solubility trends beyond the ones I have noted previously. Some intriguing ones deal with phenanthrene-9-carboxaldehyde, which has been in integral part of many of the Ugi products that were made. More products have been formed using phenanthrene-9-carboxaldehyde than any other single aldehyde.
I planned experiments 184 and 186 to see the solubility properties of previous experiments in three solvents other than methanol. In experiment 184, I repeated the starting materials from experiment 183, which did not go into solution in methanol.
I was curious to see which starting materials if any would form a clear solution in ethanol, acetonitrile, and dichloromethane. In experiment 184, phenanthrene-9-carboxaldehyde, cyclohexylamine, mandelic acid (2-hydroxy-2-phenylacetic acid) and t-butyl isocyanide were added to each of those three solvents. In Exp183, the cyclohexylamine went into solution in the methanol, but the addition of phenanthrene-9-carboxaldehyde made a cloudy solution which did not clear up with the addition or the acid and isocyanide or with vortexing. In Exp184, the vials containing ethanol and acetonitrile followed the same pattern; the addition of phenanthrene-9-carboxaldehyde made a cloudy solution. However, in the vial containing dichloromethane, a clear solution was obtained following the addition of phenanthrene-9-carboxaldehyde and vortexing for three minutes. As a result, the reagents were still insoluble in each of the three alternative solvents. This acid may not have been the best choice, because it is bulky and has eight carbon atoms. Although it is soluble in water and most organic solvents, it is insoluble in a clear mixture of methanol and cyclohexylamine.
In Exp186, I wanted to see if 1-pyrenebutyric acid would go into solution in a different solvent. I repeated the starting materials from Exp181-83, using benzaldehyde, aniline, 1-pyrenebutyric acid and n-butylisocyanide in ethanol, acetonitrile and dichloromethane. After the aniline and benzaldehyde were each added to the three solvents, clear solutions were obtained. However, once the 1-pyrenebutyric acid was added to each solution, no clear solution could be obtained after vortexing. Even with the addition of n-butylisocyanide, the three vials remained unclear.
I plan on performing a few more experiments that have been performed previously in methanol in ethanol, acetonitrile and dichloromethane. It would be interesting to repeat an experiment that produced a Ugi product in methanol.
Organization
Another important aspect of research was maintaining the organization of each aspect of all the experiments. The UgiWorkflows Google Doc needed to be updated with scripts pages for some of the previously added experiments. This is a very time consuming process, but it needs to be done. The scripts pages will hopefully be used in the future as a part of an automated process in which a robot can add pre-made solutions of each compound into vials. For each picture that is added into the UgiWorkflows table, there is also a corresponding script page which contains the amount of each compound added and the InChiKey for each one. If the Google Docs are not properly organized and formatted, they can't be optimally used, because the sorting options will not take into account any errors that were made during input. The CombiUgiResults document is also important, because it is a great way to compare the concentrations of experiments that formed a Ugi product to experiments that did not. A whole series of exploratory experiments could be built around determining the optimum concentrations to use for all of the starting materials in the table.
Conclusion
Concerning, the CombiUgi project, I have found that it is more difficult to keep up with each aspect of the experiments unless they are taken care of right away. The really convenient part about using Google documents to track each experiment is the ease of adding new columns of information. It is also a helpful way to share your experiments with other researchers and in turn use data that has been beneficial in other experiments. Because the documents can be exported from Google to a Microsoft Excel spreadsheet, it is possible to sort the data by column and find various trends. Some important trends have concerned the solubility of starting materials and the formation of solid products, and there is an opportunity for many different experiments to be performed regarding solubility and concentrations.
This research project was also a great way to learn about ChemSpider and apply it to my experiments. After becoming a member of ChemSpider, I was able to upload Ugi products onto their server. Then, all of the data for that product can be found in one place. Also, once a molecule has been saved in Chemspider, the InChi and SMILES notations can be exported into ChemSketch to make up a scheme for the reaction. It was great to learn the ways that you can tie everything together and apply various organizational techniques to your data once you've completed an experiment. The CombiUgi project has been an interesting experience where I've learned all about using a wiki, the Ugi reaction, and the useful organization of Google Docs.
Tags
furfurylamine InChI=1/C5H7NO/c6-4-5-2-1-3-7-5/h1-3H,4,6H2 InChIKey: DDRPCXLAQZKBJP-UHFFFAOYAX
Phenanthrene-9-carboxaldehydeInChI=1/C15H10O/c16-10-12-9-11-5-1-2-6-13(11)15-8-4-3-7-14(12)15/h1-10H InChIKey: QECIGCMPORCORE-UHFFFAOYAE
phenylacetic acid InChI=1/C8H8O2/c1-7(9)10-8-5-3-2-4-6-8/h2-6H,1H3 InChIKey: WLJVXDMOQOGPHL-UHFFFAOYAR
n-butyl isocyanide InChI=1/C5H9N/c1-3-4-5-6-2/h3-5H2,1H3 InChIKey: FSBLVBBRXSCOKU-UHFFFAOYAR
tert-butylisocyanideInChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3 InChIKey: FAGLEPBREOXSAC-UHFFFAOYAL
Crotonic Acid: InChI=1/C4H6O2/c1-2-3-4(5)6/h2-3H,1H3,(H,5,6)/f/h5H InChIKey: LDHQCZJRKDOVOX-UHFFFAOYAC
n-Heptylamine : InChI=1/C7H17N/c1-2-3-4-5-6-7-8/h2-8H2,1H3 InChIKey: WJYIASZWHGOTOU-UHFFFAOYAD
benzylamine InChI=1/C7H9N/c8-6-7-4-2-1-3-5-7/h1-5H,6,8H2 InChIKey: WGQKYBSKWIADBV-UHFFFAOYAL
4-chlorophenyl acetic acid InChI=1/C8H7ClO2/c9-7-3-1-6(2-4-7)5-8(10)11/h1-4H,5H2,(H,10,11)
Acetic Acid InChI=1/C2H4O2/c1-2(3)4/h1H3,(H,3,4) InChIKey: QTBSBXVTEAMEQO-UHFFFAOYAR
3,4-dihydroxyphenyl acetic acid InChI=1/C8H8O4/c9-6-2-1-5(3-7(6)10)4-8(11)12/h1-3,9-10H,4H2,(H,11,12) InChIKey: CFFZDZCDUFSOFZ-UHFFFAOYAU
Mandelic acid InChI=1/C8H8O3/c9-7(8(10)11)6-4-2-1-3-5-6/h1-5,7,9H,(H,10,11)/t7-/m0/s1 InChIKey IWYDHOAUDWTVEP-UHFFFAOYAD
4-chlorophenyl acetic acid InChI=1/C8H7ClO2/c9-7-3-1-6(2-4-7)5-8(10)11/h1-4H,5H2,(H,10,11) InChIKey: CDPKJZJVTHSESZ-UHFFFAOYAC
Tosylmethyl isocyanide InChI=1/C9H9NO2S/c1-8-3-5-9(6-4-8)13(11,12)7-10-2/h3-6H,7H2,1H3 InChIKeyCFOAUYCPAUGDFF-UHFFFAOYAC
2,3-dihydroxybenzoic acid InChI=1/C7H6O4/c8-5-3-1-2-4(6(5)9)7(10)11/h1-3,8-9H,(H,10,11) InChIKey: GLDQAMYCGOIJDV-UHFFFAOYAE
Furoic acid InChI=1/C5H4O3/c6-5(7)4-2-1-3-8-4/h1-3H,(H,6,7) InChiKey: SMNDYUVBFMFKNZ-UHFFFAOYAH
3,4-methylenedioxyphenylacetic acid InChI=1/C9H8O4/c10-9(11)4-6-1-2-7-8(3-6)13-5-12-7/h1-3H,4-5H2,(H,10,11) InChIKey: ODVLMCWNGKLROU-UHFFFAOYAB
2,4,6-trihydroxybenzoic acid: InChI=1/C7H6O5/c8-3-1-4(9)6(7(11)12)5(10)2-3/h1-2,8-10H,(H,11,12) InchiKey: IBHWREHFNDMRPR-UHFFFAOYAP
Pyrene-1-butyric acid; InChI=1/C20H16O2/c21-18(22)6-2-3-13-7-8-16-10-9-14-4-1-5-15-11-12-17(13)20(16)19(14)15/h1,4-5,7-12H,2-3,6H2,(H,21,22) InchiKey: QXYRRCOJHNZVDJ-UHFFFAOYAV